Despite enormous advances in understanding of the pathological mechanisms, the outcome of malignant brain tumors remains bleak. In part, the failure can be attributed to the inability to deliver effective and sufficient concentrations of chemotherapeutic drugs to the tumor site. The unique anatomical, physiological, and functional characteristics of brain tissue pose enormous challenges to drug delivery. A variety of formulations of chemotherapeutic drugs have been developed to better target tumor tissues, these include: conventional liposome, sterically-stabilized (Stealth) liposomes, immunoliposomes, programmable fusogenic vehicles, nanoparticles, and magnetic nanoparticles, amongst others. For optimum benefit these smart drug formulation have to be injected locally, however the kinetics of intraarterial (IA) drug delivery to the brain is ill-understood as yet due to the lack of a method to measure tissue drug concentrations in real time. Our overall goal is to improve IA delivery of liposomal formulations chemotherapeutic drugs, guided by real-time, tissue noninvasive optical methods for monitoring drug concentrations. Optical techniques we propose also permit simultaneous assessment of blood brain barrier permeability. We will identify the properties of liposomes and determine the optimum method for their IA delivery. We will develop computational models that will help translate this preclinical research to novel treatments of human brain tumors. IA injections side-step the very significant problem of rapid clearance of liposomes and nanoparticles, by the high- capacity/high affinity clearance mechanisms - mainly in the reticuloendothelial system that has prevented the development of effective liposome-based therapeutics since the late 1970's. Improved IA delivery means that a wide range of approaches, which have been rendered ineffective by systemic administration - may now be brought to bear for the treatment of malignant brain tumors. An entire range of liposomes compositions (or biophysical/biopharmaceutical properties) that were of limited utility after conventional systemic administration might be employable by improved IA injections. Using mitoxantrone as the prototype chemotherapeutic drug, our goal is to utilize optical tools to better understand the ultra-fast and complex kinetic of IA drug delivery, to use a combination of better injection techniques and smart formulations to improve regional drug delivery, and to demonstrate increased survival in experimental a rabbit brain tumor model. The twin objectives of this multi- center (Columbia University, Boston University and University of Buffalo) application are to identify improved methods of drug delivery to the brain/brain tumors, and in parallel, to develop of an integrated optical system capable of tracking tissue concentrations, blood flow, and capillary permeability parameters and safer techniques to disrupt the blood brain barrier. While this project focuses on chemotherapeutic drugs, the technologies and pharmacokinetic insights it will generate will have applications beyond treatment of brain cancers. PUBLIC HEALTH RELEVANCE: The overall goal of this project is to improve intraarterial (IA) delivery of liposomal formulations of chemotherapeutic drugs, guided by real-time, tissue noninvasive optical methods for monitoring drug concentrations. Optical techniques we propose also permit simultaneous assessment of blood brain barrier permeability. We will identify the properties of liposomes and determine the optimum method for their IA delivery. Furthermore, we will develop computational models that will help translate this preclinical research to novel treatments of human brain tumors.